1. Field of the Invention
This invention relates to derivatives of butanedioic acid. More particularly this invention relates to compounds having the formula ##STR2## wherein R.sup.1 is hydrogen or methyl, R.sup.2 is hydrogen or lower alkyl and their pharmaceutically acceptable salts. These compounds have .beta.-adrenergic blocking activity.
2. Description of the Prior Art
U.S. Pat. No. 3,337,628 describes 1-isopropyl-amino-3-(1-naphthoxy)-2-propanol (propranolol). This compound or the pharmaceutically acceptable salt of this compound can be used as the precursor in the synthesis of one of the presently claimed compounds. Additionally, U.S. Pat. No. 3,337,628 discloses that propranolol can be used in the treatment of coronary artery disease and specifically as a .beta.-adrenergic blocking agent. However, a major drawback of compounds disclosed in U.S. Pat. No. 3,337,628 and particularly propranolol is that because of extensive metabolism, little unchanged active material reaches the systemic circulation after oral administration. Additionally, plasma levels of propranolol show a large patient to patient variation.
The prior art contains the following theories as to the disposition of propanolol when taken orally:
1. Substantial amounts of propanolol are converted to the glucoronide during the absorption process and enters enterohepatic circulation.
2. Free propranolol absorbed from the G.I. Tract into the portal vein is distributed in the liver depending on the absorption rate and the dose of propanolol. Matabolites formed in the liver are probably converted to the conjugated glucuronide form.
3. Conjugated propranolol is not excreted rapidly into the urine. The major part of the conjugated form of propranolol is excreted in bile. Although the detailed process of the fate of the conjugated propranolol excreted in bile, is not known it might be reasonable to assume the following steps.
(1) The bile is concentrated at the gall bladder, the conjugated propranolol is partially absorbed from bile into the systemic circulation. PA1 (2) Most of the glucuronide is excreted into the G.I. Tract, probably hydrolyzed by enzymatic action and reabsorbed. The enterohepatic circulation of propranolol constitutes a hidden depot in the body.
4. The metabolites are excreted in urine as conjugated forms.
It has now been discovered that the extent of the above forms of metabolism in the G.I. tract and/or the liver can be markedly reduced when the compounds of this invention are employed. While not wishing to be bound by any theory, it is believed that the compounds of this invention are especially effective since they protect the .beta.-adrenergic blocking compound from extensive metabolism during absorption and are rapidly hydrolyzed after absorption to release the active compound into the blood.